McCune-Albright syndrome (MAS) is a non-inherited disorder in which affected subjects show a variety of seemingly unrelated abnormalities including polyostotic fibrous dysplasia, pigmented skin lesions (cafe-au-lait spots), and autonomous hyperfunction of various endocrine organs including gonads, anterior pituitary, thyroid, and adrenal cortex. The endocrine abnormalities lead to precocious puberty, gigantism/acromegaly, hyperthyroidism, and hypercortisolism. The cause of this sporadic disorder has been enigmatic, but speculations have centered on a defect in signal transduction leading to endocrine hyperfunction. The distribution of skin lesions has also suggested the possibility of a somatic mutation acquired early in embryogenesis and affecting only a subset of cells (mosaicism). Since a G protein mutation could plausibly explain the endocrine manifestations, we searched for and found mutations of the Gs-alpha gene that lead to constitutive activation of the Gs protein. These mutations were found in a mosaic distribution; notably, mutant gene was undetectable in normal-appearing portions of endocrine glands, but was present at heterozygous levels in neoplastic portions of endocrine tissue. Mutant Gs-alpha was also detected in dysplastic bone lesions, both in the polyostotic, "classical" form of MAS and in a "form fruste" of the disease, monostotic fibrous dysplasia. Occurrence of mutant Gs-alpha in organs such as heart and liver suggest a possible role in "non-classical" manifestations, including sudden death. Our studies suggest that MAS is caused by a somatic mutation in the Gs-alpha gene occurring early in development and found in a mosaic distribution. More focal manifestations of the disease such as monostotic fibrous dysplasia may be caused by somatic mutation of the Gs-alpha gene occuring later in development. To define the pathogenesis of the dysplastic bone lesions, we have pursued studies in primary cultured cells from bone lesions of patients with MAS. The latter have been cloned into distinct populations of mutant-positive and mutant negative-cells and have been used for in vitro studies, and in vivo studies in a nude mouse model implanted with human bone cells (with P. Robey, NIDR). The latter recapitulates the fibrous dysplasia lesion when mutant cells are implanted. These studies should be useful for identifying treatments that might eventually be used in patients.